Antiviral Mechanisms & Resistance

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Questions and Answers

Why do treatments for RNA viruses, such as HIV and Hepatitis C, commonly involve multiple antiviral agents?

  • To counteract the higher mutation rates of RNA viruses, making it more difficult for the virus to develop resistance. (correct)
  • To target multiple host cell metabolic pathways simultaneously, limiting viral replication and spread more effectively.
  • To directly inhibit the proofreading mechanisms of RNA viruses, preventing any mutations from arising during replication.
  • To enhance the individual efficacy of each antiviral agent through synergistic effects, leading to faster viral clearance.

What is the most common mechanism of resistance to Acyclovir in herpes simplex virus (HSV)?

  • Decreased cellular uptake of Acyclovir due to mutations in viral entry proteins.
  • Overexpression of viral DNA polymerase, overwhelming the inhibitory effects of the drug.
  • Mutations leading to a deficiency in virus-induced thymidine kinase, preventing initial drug activation. (correct)
  • Mutations in the host cell kinases responsible for activating Acyclovir, preventing phosphorylation.

How does selective pressure contribute to the development of antiviral resistance?

  • By inducing epigenetic changes in the viral genome, leading to increased stability and drug resistance.
  • By directly accelerating the rate of viral replication, leading to increased mutation rates.
  • By creating an environment where only the most resistant viral strains can survive and replicate. (correct)
  • By inhibiting the host's immune response, allowing the virus to replicate unchecked and develop resistance.

Which detection method would provide the earliest indication of antiviral resistance?

<p>Genotypic resistance, detecting specific genetic mutations in the virus. (A)</p> Signup and view all the answers

Why is medication adherence critical for preventing HIV drug resistance?

<p>Regular dosing ensures the virus is constantly suppressed, preventing resistance mutations. (B)</p> Signup and view all the answers

How do changes in viral neuraminidase contribute to resistance against neuraminidase inhibitors used for influenza treatment?

<p>By altering the structure of neuraminidase, reducing the drug's ability to bind and inhibit the enzyme. (A)</p> Signup and view all the answers

What is the role of the UL97 kinase in Ganciclovir's mechanism of action, and how do mutations in this kinase lead to resistance?

<p>UL97 kinase activates Ganciclovir; mutations prevent this activation, rendering the drug ineffective. (A)</p> Signup and view all the answers

How does the S282T substitution in the NS5B gene confer resistance to Sofosbuvir in Hepatitis C virus (HCV)?

<p>By reducing the effectiveness of Sofosbuvir in inhibiting viral replication. (D)</p> Signup and view all the answers

Why are single-stranded RNA viruses, like HIV and influenza, more prone to developing drug resistance compared to DNA viruses?

<p>They lack effective proofreading mechanisms, leading to higher mutation rates. (A)</p> Signup and view all the answers

Which factor does NOT directly contribute to the increased emergence of antiviral resistance?

<p>The inherent stability of viral genomes, preventing mutations. (A)</p> Signup and view all the answers

Flashcards

Antiviral Mechanisms

Antiviral actions target virus-unique replication events, differing from human cell mechanisms.

RNA viruses

RNA viruses mutate faster because they lack proofreading, requiring multiple agents to prevent resistance.

Herpes antiviral resistance

Herpes drugs like Acyclovir need activation via phosphorylation; mutations prevent this, causing resistance.

Factors increasing resistance

Faster viral replication increases mutation chances. High drug exposure accelerates resistance. RNA viruses mutate rapidly.

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Antiviral resistance detection

Manifestations (phenotype), genetic indicators (genotype), viral load changes (quantification).

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HIV resistance decline

Better medications and patient adherence have decreased high-level resistance.

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Acyclovir activation

Acyclovir requires three-step activation involving viral thymidine kinase; mutations here cause resistance.

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Neuraminidase Inhibitors

Changes in neuraminidase or hemagglutinin allows resistance to occur.

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Hepatitis C resistance

Mutations the NS5B gene prevents the RNA polymerase from being inhibited.

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Study Notes

Antiviral Mechanisms

  • Antivirals target replication events specific to viruses, unlike antibiotics
  • They may affect metabolic events shared by both the host cell and the virus, such as DNA, RNA, or protein synthesis

RNA vs. DNA Viruses

  • RNA viruses mutate more frequently than DNA viruses
  • HIV and Hepatitis C are examples of RNA viruses, and are typically treated with multiple agents to prevent resistance

Mechanisms of Resistance

  • Resistance is well-understood due to intense study of viral genomes and replication
  • Acyclovir and Ganciclovir, used to treat herpes, the mutations on the enzyme responsible for phosphorylating the drug; if the drug cannot become active, it cannot inhibit the virus

Factors Increasing Antiviral Resistance

  • Rate of Viral Replication: Faster replication leads to more mutations
  • Selective Pressure: Frequent antiviral use increases resistance
  • Rate of Viral Mutations: Single-stranded RNA viruses like HIV and influenza mutate rapidly

Detection of Antiviral Resistance

  • Phenotypic Resistance: Manifestations of the disease. For example, in HIV, declining CD4 count and opportunistic infections
  • Genotypic Resistance: Detecting genetic mutations indicating resistance
  • Quantification of Response: Assessing viral load. In HIV, increasing viral load indicates resistance before the CD4 count drops

Challenge of HIV Medication Resistance

  • All classes of HIV medications have shown resistance
  • High-level resistance has been declining because of better and better-tolerated medications
  • Medication adherence is crucial for preventing HIV drug resistance

Acyclovir Activation

  • Requires a three-step activation process, beginning with conversion to the monophosphate derivative by viral thymidine kinase
  • If thymidine kinase enzyme is mutated, it cannot phosphorylate (activate) Acyclovir.
  • Acyclovir cannot inhibit viral DNA polymerase without activation

Neuraminidase Inhibitors (Influenza)

  • Resistance happens when there are mutations in the viral neuraminidase enzyme
  • Changes in hemagglutinin can also contribute to resistance

Ganciclovir (Cytomegalovirus - CMV)

  • Linked to mutations in the viral gene CMV UL97
  • Mutations in UL97 prevent proper activation of the drug, rendering it ineffective

Sofosbuvir (Hepatitis C)

  • Resistance is conferred by substitutions in the NS5B gene of the virus

Acyclovir (Herpes Simplex Virus - HSV)

  • The most common mechanism of resistance is a deficiency of the virus-induced thymidine kinase (TK).
  • Over 50% of HSV strains resistant to Acyclovir lack the thymidine kinase enzyme (TK-deficient strains).

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